Valve

ABSTRACT

A luminal valve for placing in a body lumen comprises at least four valve leaflets. The valve has a normally closed configuration in which the leaflets are engaged and an open configuration in which the leaflets are open. The valve may be mounted to an esophageal support.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication No. 61/074,393 filed Jun. 20, 2008; 61/074,400 filed Jun.20, 2008; 61/145,337 filed Jan. 16, 2009; 61/145,332 filed Jan. 16,2009; 61/151,968 filed Feb. 12, 2009; 61/151,973 filed Feb. 12, 2009;61/174,536 filed May 1, 2009; and 61/181,043 filed May 26, 2009, theentire contents of all of which are incorporated herein by reference.

INTRODUCTION

An esophageal stent is often placed across the lower esophagealsphincter (LES) to treat benign strictures or malignant obstructions.However, the consequent loss of a reflux barrier often results insignificant amounts of acid reflux, which can reduce the quality of lifeof an already sick patient.

Such esophageal stents that are placed across the gastric cardia aresometimes equipped with a flexible sleeve that hangs below the stentinto the stomach. These so called ‘windsock’ devices rely on theslightly increased pressure of the stomach to flatten and close thesleeve.

However, there are a number of problems with existing in-stent refluxtechnology. When a patient wishes to belch or vomit many of thesedevices will seal completely preventing retrograde flow and causing thepatient significant discomfort. In some cases the sleeves can invert toallow retrograde flow but may then remain inverted and may causeblockage of the esophagus. In addition, because such sleeves aregenerally at the distal end of the stent where peristalsis is noteffective, there is a risk of food becoming stuck in this portion of thedevice. Another problem is that the materials that these valves are madefrom often degrade in the gastric environment thus reducing the efficacyof the devices over time.

STATEMENTS OF INVENTION

According to the invention there is provided an esophageal valve having:

-   -   a normally closed configuration in which the valve is closed;    -   an antegrade open configuration in which the valve leaflets are        opened in response to an antegrade force to allow flow through        the valve; and    -   a retrograde open configuration in response to an retrograde        force which is substantially larger than the antegrade force.

In one embodiment the valve comprises a polymeric valve body having anouter support rim, at least three valve leaflets, and a main body regionextending between the support rim and the valve leaflets.

The invention also provided a luminal valve for placing in a body lumencomprising at least four valve leaflets, the valve having a normallyclosed configuration in which the leaflets are engaged and an openconfiguration in which the leaflets are open. There may be at least fivevalve leaflets. There may be six valve leaflets.

In one case the valve is an esophageal valve. In one case the valve hasan antegrade open configuration in which the valve leaflets are openedin response to an antegrade force to allow flow through the valve and aretrograde open configuration in response to a retrograde force which issubstantially larger than the antegrade force.

The valve may comprise a valve body of polymeric material. The valve maycomprise an outer support region. The valve may also have a main bodyregion extending between the support region and the valve leaflets.

In one case the main body region is generally concave between the outersupport rim and a region of co-aption of the valve leaflets.

In one embodiment the valve leaflets and at least portion of the mainbody region inverts to allow flow in the retrograde direction.Preferably, on reduction in retrograde forces the main valve region andthe valve leaflets evert to the normally closed configuration.

In one case the valve leaflets have a region of co-aption and the valvebody is reinforced at the region of co-aption. The valve body may bethickened at the region of co-aption.

The region of co-aption may extend for an axial length of at least 1 mm.The region of co-aption may extend for a depth of from 1 mm to 5 mm.

In one embodiment the support rim of the valve body is reinforced. Thesupport rim of the valve may be thickened.

In one embodiment the valve comprises three valve leaflets.

In another embodiment the valve comprises six valve leaflets.

The invention also provides an esophageal valve comprising a supportstructure for the valve.

The valve may be mounted to the support structure.

In one case the valve rim is sutured to the support structure.Alternatively or additionally the valve rim is bonded to the supportstructure.

In one embodiment the support structure comprises a luminal prosthesis.

In one case the luminal prosthesis extends proximally of the valve.

In another case the luminal prosthesis extends distally of the valve.

In one embodiment the luminal prosthesis extends proximally and distallyof the valve.

The luminal prosthesis may have a coating and/or a sleeve thereon. Thecoating or sleeve may be on the outside of the luminal prosthesis.Alternatively the coating or sleeve is on the inside of the luminalprosthesis.

In one embodiment a pressure of 0.7 mm Hg in the antegrade direction issufficient to allow a flowrate of 140 ml/min.

In one embodiment the retrograde force required to open the valve is apressure of greater than 15 mm Hg and less than 40 mm Hg.

In one embodiment the polymeric material is stable to gastric fluid forat least 3 months, for at least 4 months, for at least 5 months, for atleast 6 months, for at least 7 months, for at least 8 months, for atleast 9 months, for at least 10 months, for at least 11 months, or forat least one year.

In one case the polymeric material takes up less than about 5%, lessthan about 10%, less than about 15%, less than about 20%, less thanabout 25%, or less than about 30% by weight of water at equilibrium.

In one case the polymeric material of the valve body has a % elongationof from 50% to 3000% or 200% to 1200%.

In one case the polymeric material of the valve body has a tensilestrength of from 0.01 to 5 MPa or about 0.1 to 1.0 MPa, or about 0.25 to0.5 MPa.

In one embodiment the polymeric material has a Young's Modulus of about0.01 to 0.6 MPa, or about 0.1 to about 0.5 MPa.

In one embodiment the polymeric material of the valve body has a densityof from 0.1 g/cm³ to 1.5 g/cm³, or 0.3 to 1.2 g/cm³, or 0.8 to 0.9g/cm³, or 0.5 to 0.6 g/cm³.

In one embodiment the distance between the proximal end of the supportregion of the valve body and the distal end of the valve leaflets isless than 50 mm, or less than 40 mm, or less than 30 mm, or less than 25mm, or less than 20 mm, or less than 15 mm.

In one case the polymeric material of the valve body is of an elasticmaterial.

In another case the polymeric material of the valve body is of aviscoelastic material.

In one embodiment the polymeric material of the valve body comprises afoam. The polymeric material of the valve body may comprise an open cellfoam.

In one embodiment the polymeric material of the valve body comprises apolyurethane foam.

In one embodiment the esophageal valve is adapted to be mounted to apre-deployed support structure, for example an esophageal luminalprosthesis such as a stent.

The invention also provides a valve having:

-   -   a normally closed configuration in which the valve is closed;    -   an open configuration in which the valve is opened for flow        through the valve; and    -   a support for the valve, the support being adapted for mounting        to a pre-deployed luminal prosthesis intermediate a proximal end        and a distal end of the predeployed luminal prosthesis.

In one case the valve is an esophageal valve for mounting to anesophageal stent.

In one embodiment the valve support region is sutured to the supportstructure.

The valve support region may be bonded to the support structure.

The luminal prosthesis may extend proximally of the valve. The luminalprosthesis may extend distally of the valve. The luminal prosthesis mayextend proximally and distally of the valve.

In one case the luminal prosthesis has a coating and/or sleeve thereon.The coating or sleeve may be on the outside of the luminal prosthesis.Alternatively or additionally the coating or sleeve is on the inside ofthe luminal prosthesis.

In one embodiment the valve is adapted to be mounted to a pre-deployedesophageal luminal prosthesis such as an esophageal stent.

There may be a mounting means for mounting the valve to a pre-deployedesophageal luminal prosthesis. The mounting means may be provided on thevalve.

In one case the mounting means comprises engagement means for engagementwith a pre-deployed stent.

The valve may comprise a support structure. The support structure maytaper outwardly or inwardly.

In one case the support structure is of generally uniform diameter alongthe length hereof.

In one embodiment the support structure comprises a scaffold. Thesupport structure may comprise a stent-like structure.

The mounting means may be provided by the support structure. In one casethe mounting means comprises protrusions extending from the supportstructure. The protrusions may be adapted to engage with a pre-deployedhost esophageal luminal prosthesis.

In one embodiment the protrusion comprises a loop.

In one case the apicial tip of the protrusion is rounded.

The protrusions may be releasably engagable with a pre-deployed hostesophageal luminal prosthesis.

There may be release means for releasing the valve from engagement witha pre-deployed host esophageal luminal prosthesis. The release means maycomprise means for reducing the diameter of at least portion of thevalve support structure.

In one case the release means comprises a drawstring extending aroundthe valve support structure. A first drawstring may extend around aproximal end of the support structure. A second drawstring may extendaround a distal end of the support structure.

In one embodiment the valve is mounted to the support structure. Thevalve may be sutured to the support structure. The valve may be bondedto the support structure. The valve may be adhesively bonded to thesupport structure.

In another case the mounting means comprises a surgical adhesive.

The invention also provides a method for providing a valve in a bodypassageway comprising the steps of:

-   -   providing a valve mounted to a support structure;    -   delivering the valve mounted to the support structure to a        pre-deployed luminal prosthesis in the body passageway; and    -   deploying the valve so that the valve is mounted to the luminal        prosthesis.

In one embodiment the step of deploying the valve comprises engaging thevalve support with the pre-deployed luminal prosthesis.

The valve support may be mechanically engaged with the pre-deployedluminal prosthesis.

In one case the valve support comprises a protrusion and the methodcomprises aligning the protrusion with an aperture in the endoluminalprosthesis and engaging the protrusion in the aperture.

In one embodiment the valve support is an expandable support and themethod comprises loading the support onto a delivery catheter in aretracted form and the valve support is extendable on deployment.

The support may be self expandable or the support is expanded by anexpanding means such as a balloon.

In one embodiment the method comprises the step of releasing the valvesupport from engagement with the luminal prosthesis.

The method may involve repositioning the valve support within theprosthesis. The method may comprise removing the valve from theprosthesis.

In one embodiment the body passageway is the esophagus and the valve isan esophageal valve for mounting to a pre-deployed esophageal stent.

In one case there is a support structure for the valve. The valve may bemounted to the support structure. The valve support region may besutured to the support structure. Alternatively or additionally thevalve support region is bonded to the support structure. In one case thesupport structure is overmoulded to the valve support region.

The support structure may comprise a luminal prosthesis.

In one embodiment the luminal prosthesis extends proximally of thevalve. The prosthesis may comprise a self expanding plastics mesh. Theprosthesis may apply a radial force of less than 1.9 kPa.

In one embodiment there are anchors for mounting the prosthesis in situ.The anchors may be adapted to extend through the mesh of the prosthesis.

In one case the prosthesis is adapted to be anchored to the cardia.

In one embodiment the length of the valve from the proximal end of thesupport region to the distal end of the valve leaflets is less than 50mm, less than 40 mm, less than 30 mm. The length of the valve may beapproximately the same as the outer diameter of the support region ofthe valve. The length of the valve may be approximately 23 mm.

In another aspect the invention comprises a method for treatinggastroesophageal reflux disease comprising providing a valve of theinvention and placing the valve at a desired location. The desiredlocation may be across the lower esophageal sphincter. In one case thevalve leaflets are located distal to the end of the esophagus. In oneembodiment the valve is provided with a support structure and the methodcomprises mounting the support structure at the desired location. Themethod may comprise anchoring the support structure to the body wall atthe desired location. In one case the method comprises anchoring thesupport structure to the cardia.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more clearly understood from the followingdescription thereof given by way of example only, in which:

FIG. 1 is an isometric view (from above) of an esophageal valveaccording to the invention;

FIG. 2 is an isometric view (from below) of the esophageal valve;

FIG. 3 is a top plan view of the valve;

FIG. 4 is an underneath plan view of the valve;

FIGS. 5 and 6 are elevational views of the valve;

FIGS. 7 and 8 are isometric, partially cut-away sectional, views of thevalve;

FIGS. 9 and 10 are cross sectional views of the valve;

FIG. 11 is a cross sectional view of the valve in a normally closedconfiguration with an antegrade force applied;

FIG. 12 is a cross sectional view of the valve in an open configurationin response to an antegrade force;

FIG. 13 is a cross sectional view of the valve returned to the closedconfiguration after opening to antegrade flow;

FIG. 14 is a cross sectional view of the valve in a normally closedconfiguration with a retrograde force applied;

FIG. 15 is a cross sectional view of the valve in an open configurationin response to retrograde force;

FIG. 16 is a cross sectional view of the valve returned to the closedconfiguration after opening to retrograde flow;

FIG. 17 is an isometric view (from above) of the valve in a normallyclosed configuration;

FIG. 18 is an isometric view of the valve in a partially openconfiguration in response to an antegrade force;

FIG. 19 is an isometric view of the valve in a fully open configurationin response to antegrade force;

FIG. 20 is an isometric view (from below) of the valve in a normallyclosed configuration;

FIG. 21 is an isometric view of the valve moving towards an openconfiguration in response to a retrograde force;

FIG. 22 is an isometric view of the valve in a fully open configurationpermitting retrograde flow;

FIG. 23 is an isometric view of a esophageal prosthesis;

FIG. 24 is an elevational view of the valve of FIGS. 1 to 22 beingmounted to and in position on the prosthesis of FIG. 23;

FIG. 25 is another view of the valve mounted in a prosthesis;

FIGS. 26 and 27 are isometric views of a sleeved or coated esophagealprosthesis;

FIG. 28 is an isometric view of the prosthesis of FIGS. 26 and 27 with avalve of FIGS. 1 to 22 in position;

FIG. 29 is an elevational view of part of the prosthesis of FIG. 28 inposition in the esophagus;

FIG. 30 is an isometric view of a valve according to another embodimentof the invention;

FIG. 31 is an elevational view of the valve of FIG. 30;

FIG. 32 is an isometric view of another valve according to the inventionwith a distally outward tapering support structure;

FIG. 33 is an elevational view of the valve of FIG. 32.

FIG. 34 is an isometric view of another valve according to the inventionwith a distally inward tapering support structure;

FIG. 35 is an elevational view of a luminal prosthesis with a valve andassociated support structure in place;

FIG. 36 is an enlarged view of the luminal prosthesis and valve supportstructure of FIG. 35;

FIGS. 37 and 38 are enlarged views of one mounting detail of a valvesupport structure to a luminal prosthesis;

FIGS. 39 to 43 are views of a valve being deployed from a deliverycatheter;

FIGS. 44 to 46 are views of a luminal prosthesis in place in theesophagus with a valve being deployed in the lumen of the luminalprosthesis.

FIG. 47 is an elevational view of a valve according to anotherembodiment of the invention;

FIG. 48 is an enlarged view of a detail of the support structure of thevalve of FIG. 47;

FIGS. 49 and 50 are isometric views of the valve of FIGS. 47 and 48being deployed from a delivery catheter;

FIG. 51 is an elevational view of a prosthesis with the valve of FIGS.49 to 50 in situ;

FIG. 52 is an enlarged view of a detail of the engagement of the valvesupport structure of FIGS. 47 to 51 engaged in the mesh of theprosthesis;

FIG. 53 is an enlarged view of part of the luminal prosthesis and valvesupport structure of FIG. 52.

FIG. 54 is an elevational view of an esophageal luminal prosthesis;

FIG. 55 is an elevational of an esophageal valve of the invention;

FIGS. 56 to 61 are elevational views of steps involved in deploying thevalve of FIG. 55 into a pre-deployed esophageal luminal prosthesis ofFIG. 54;

FIG. 62 is an elevational view of the valve of FIG. 55 deployed in theluminal prosthesis of FIG. 61;

FIG. 63 is an elevational view similar to FIG. 62 with the valve beingremoved from the deployed prosthesis;

FIGS. 64 and 65 are isometric view of another valve according to theinvention;

FIG. 66 is a top plan view of the valve of FIGS. 64 and 65;

FIG. 67 is an underneath plan view of the valve of FIGS. 64 and 65;

FIG. 68 is an elevational view of the valve of FIGS. 64 and 65;

FIG. 69 is a cross sectional view of the valve of FIGS. 64 and 65;

FIG. 70 is a cut-away isometric view of the valve of FIGS. 64 and 65;

FIG. 71 is an isometric view of a valve and an associated support;

FIG. 72 is an elevational view of the valve and support of FIG. 71;

FIG. 73 is a plan view of the device of FIGS. 71 and 72 with the valvein a closed configuration;

FIG. 74 is a plan view similar to FIG. 73 with the valve in an openconfiguration;

FIGS. 75 and 76 are side views of the device of FIG. 73 with the valvein a closed configuration;

FIGS. 77 and 78 are side views of the device of FIG. 73 with the valvein the open configuration;

FIG. 79 is a cross sectional view of the device of FIG. 72 in use in aclosed configuration;

FIG. 80 is a view similar to FIG. 79 with the device anchored at thedesired location;

FIG. 81 is a cross sectional view of the device in a closedconfiguration;

FIG. 82 is a cross sectional view of the device with the valve in theretrograde open configuration;

FIG. 83 is an elevational view of another device similar to FIG. 71;

FIG. 84 is a plan view of the device of FIG. 83;

FIG. 85 is an illustration of prior art polymers with urea and urethanelinkages interspersed between homopolymer soft segments;

FIG. 86 is an illustration of a polyurethane/urea foam according to theinvention with urea and urethane linkages interspersed between triblockcopolymer soft segments;

FIG. 87 is an illustration of a siloxane and polypropylene oxide basedtriblock copolymer in different forms;

FIG. 88 is a graph of comparative mechanical properties of homo(VF130309) and triblock copolymer (VF230209A) soft segments;

FIG. 89 is a graph of comparative mechanical properties of home(VF190309) and triblock copolymer (VF090309) soft segments;

FIG. 90 is a graph illustrating the mechanical performance of triblockcopolymer soft segments versus homopolymer soft segment duringaccelerated aging in simulated gastric fluid;

FIG. 91 depicts a gastric yield pressure test apparatus as utilized inExample 10; and

FIG. 92A and FIG. 92B depict results of accelerated stability of a valveprepared from a viscoelastic foam of the present invention.

DETAILED DESCRIPTION

Referring to the drawings and initially to FIGS. 1 to 22 thereof thereis illustrated an esophageal valve 1 which can open automatically in theantegrade direction (food intake) and in the retrograde direction (fromthe stomach to the mouth).

The valve 1 comprises a polymeric valve body having a proximal outersupport region with a rim 2, at least three valve leaflets 3, 4, 5, anda main body region 6 extending between the support rim 2 and the valveleaflets 3, 4, 5. The valve leaflets 3, 4, 5 extend inwardly anddistally and terminate at distal end faces 7, 8, 9 respectively. Theleaflets each 3, 4, 5 have legs a, b which extend at an included angleof 120° to each other. The adjacent pairs of legs 3 a; 4 a; 4 b; 5 b; 5a; 3 b; co-apt to close the gap between the valve leaflets when thevalve is in the normally closed configuration.

The valve 1 has three configurations. The first configuration is anormally closed configuration in which the valve leaflets 3, 4, 5 co-aptto close the valve. The second configuration is an antegrade openconfiguration in which the valve leaflets 3, 4, 5 are opened such thatthe leaflet leg pairs 3 a; 4 a; 4 b; 5 b; 5 a; 3 b are opened andspaced-apart in response to an antegrade force F1 to allow flow throughthe valve. The third configuration is a retrograde open configuration inresponse to a retrograde force which is substantially larger than theantegrade force F2.

The various configurations of the valve 1 are illustrated in FIGS. 11 to22. In the first or normally closed configuration (FIGS. 11, 17) thevalve leaflets 3, 4, 5 co-apt. When an antegrade force F1 is applied tothe valve leaflets 3, 4, 5 the leaflet legs pairs 3 a; 4 a; 4 b; 5 b;and 5 a; 3 b open to allow antegrade flow to pass (FIGS. 12, 19). FIG.18 illustrates a partially open configuration in response to antegradeflow. When the antegrade force F1 is removed the leaflets 3, 4, 5 returnto the closed position under the inherent biasing of the polymericmaterial of the valve body (FIG. 13).

When a retrograde force F2 is applied to the valve body. This forceinitially pushes the valve leaflets 3, 4, 5 against one another and ifthe pressure is greater than a set value, the valve body will invert.The start of inversion is illustrated in FIG. 21. When the valve isfully opened in response to retrograde force the valve main body (andthe leaflets 3, 4, 5) extend proximally (upwardly) as illustrated inFIGS. 15 and 22. This allows retrograde flow to pass through the valve.When the retrograde force F2 is removed the valve main body will returnto the original configuration by everting in response to the biasing ofthe polymeric material to return to the normally closed configurationwith the valve leaflets extending distally as illustrated in FIGS. 16and 20.

The valve leaflets 3, 4, 5 are reinforced in the region of co-aption. Inthis case, this is achieved by a local thickening of the polymericmaterial in this region. Similarly the support rim 2 is reinforced by alocal thickening of the polymeric material.

The region of co-aption of the valve leaflets 3, 4, 5 has an axialextent which is typically from 1 to 5 mm. This ensures positiveco-aption of the leaflets across a significant interfacial area when thevalve is in the normally closed configuration. The thickness of theleaflets at the region of co-aption is typically between 0.1 mm and 10mm.

The valve body has a generally concave outer face and a generally convexinner face.

The valve 1 is a two-way valve. Different forces are required to openthe valve from the proximal or distal directions. The valve 1 requiresvery little force to open in the antegrade direction, a pressure of 0.7mm Hg in the antegrade direction is sufficient to allow a flowrate of140 ml/min. In the retrograde direction the valve 1 can hold pressuresof between 15 mmHg and 40 mmHg and higher. By varying the properties(such as density) of the material of the valve the valve can be tailoredto accommodate varying yield pressures. The valve accomplishes this bycontrollably inverting when placed under pressure in the retrogradedirection.

The valve 1 of the invention returns to its original working positionafter being fully opened in the retrograde direction. This isaccomplished without damaging the working valve.

When the valve is opened by food passing in the antegrade direction theleaflets open. The outer face of the valve has a greater resistance tochange in shape and thus the force required to open main body in theretrograde direction is higher.

The important characteristics influencing the functioning of the valveare the leaflet legs that impinge on one another. By varying thegeometry and length of the leaflets 3, 4, 5 the valve 1 can be made toopen in the retrograde direction at different pressures. Opening in theantegrade direction is somewhat less dependant on the geometry of theleaflets and more dependant on the elasticity and density of thematerial the device is made from. Additionally, the overall diameter andthe diameter to which the leaflets open influence the opening force inboth directions.

Because the stomach tends to have a slightly higher pressure than theesophagus (the difference on average being approximately 12 mmHg), aclosed valve will experience this pressure at its distal surface. Thisdistal pressure can ammeliorate the closing of a distally extending ortapering surface. However, previous examples of valves in the literaturehave relied on smooth surfaces to take advantage of this gastricpressure differential. Thus the only means of maximising the forcegenerated by the gastric pressure was to increase the length of thedistally extending or tapering surface. This in turn gave rise toproblems associated will elongate structures becoming blocked withantegrade food flow and retrograde flow. The current invention teaches amethod of retaining the short length of the valve structure andmaximising the force generated by the gastric pressure through anincrease in the surface area to length ratio. This is achieved byincreasing the surface area of the distal surface of the valve byintroducing pleats or folds (leaflets).

The valve may be of any suitable biocompatible polymeric material. Itmay be of a biocompatible polymeric material having properties whichallow the valve to function as described.

The materials used for the production of this valve have a % elongationbetween 50% and 3000%. The material also has a tensile strength ofbetween 0.01 and 5 MPa. Addionally the material could have anantimicrobial action to prevent colonisation when in-vivo. Additionallythe material can be elastic or viscoelastic and can optionally be anopen cell foam. The density of the material should be between 0.1 g/cm3to 1.5 g/cm3.

The valve of the invention may be mounted to any suitable luminalprosthesis, especially an esophageal prosthesis or stent. The rim 2 ofthe valve provides a mounting ring for mounting within the stent 20, forexample, the valve 1 may be mounted to the stent by suturing the rim 2to the stent mesh using sutures 21 as illustrated in FIGS. 24 and 25.

The stent may be of any suitable type. An uncoated or unsleeved stent 20is illustrated in FIGS. 23 to 25. Alternatively, if it is desired toprevent tissue ingrowth a stent 30 having a sleeve 31 may be used (FIGS.26 to 29). In this case the sleeve 31 is external of the stent. In othercases there may alternatively or additionally be an internal sleeve.Further, the stent may have a coating.

A valve such as described above may also be placed into a pre-deployedluminal prosthesis. For example, the valve may be an esophageal valvefor placement into a pre-deployed stent in the esophagus.

In one case a valve 100 may have a co-axial support structure orscaffold 102 is shown in FIGS. 30 and 31. The scaffold 102 is designedto engage with any suitable esophageal stent 140 as illustrated in FIG.35. The mechanism of engagement can be by protrusions which may forexample be proximal and/or distal apices 103 of the scaffold 102 whichengage into the mesh of the existing pre-deployed stent 140.Alternatively or additionally, the scaffold 102 may have features 150designed to hook onto the inside of the struts of an esophageal stent asillustrated in FIGS. 37 and 38.

Referring to FIGS. 32 and 33 there is illustrated a valve 110 accordingto another embodiment of the invention in which the support structure orscaffold 102 tapers distally outwardly so that distal apices 111 of thescaffold engage with the mesh of the existing pre-deployed host stent140.

Referring to FIG. 34 there is illustrated another valve 120 according tothe invention in which the support structure or scaffold 102 tapersdistally inward so that proximal apices 121 of the scaffold 102 engagewith the mesh of an existing pre-deployed stent 140.

The radial force of the scaffold 102 may exert enough friction to holdthe valve in place without the necessity for protrusion. In anotherembodiment a surgical adhesive may be used to secure the retrofittedvalve into place.

Referring to FIGS. 39 to 43 a valve 100 is loaded into a delivery system130 for deployment. The outer diameter of the delivery system 130 issmaller than the inner diameter of a pre-deployed esophageal stent 140.The delivery system 130 in this case comprises a delivery catheterhaving a distal pod 131 in which a valve is housed in a contractedconfiguration. The catheter has a tapered distal tip 132 to avoidsnagging on a pre-deployed stent 140. The pod 131 is axially movablerelative to the tip 132 to release the valve from the pod 131.

The delivery system 130 is used to deliver the valve to a pre-deployedstent 140 as illustrated in FIG. 44. The stent 140 has a mesh and thescaffold of the valve is adapted to engage with the mesh of thepre-deployed stent 140 on release of the valve from the deliverycatheter as illustrated particularly in FIGS. 45 and 46.

Referring to FIGS. 35 to 38 there is illustrated an idealised stent 140with a valve support scaffold 102 in situ. Details of a valve areomitted from these drawings for clarity. In this case the scaffold 102is located at the upper proximal end of the stent. In this case thescaffold 102 has hook-like members 150 for engagement with the mesh ofthe stent 140 as illustrated in FIGS. 37 and 38. The interengagementbetween the stent 140 and the scaffold 102 ensures that the scaffold 102and hence the valve which is fixed to it is retained in position andprovides an anti-proximal migration mechanism.

In the cases illustrated the valve supporting scaffold 102 is of a selfexpanding material such as a shape memory material, for example Nitinol.The valve and scaffold are loaded into the delivery catheter pod 131 ina compressed/reduced diameter configuration. When the constraint of thepod 131 is removed at the deployment site, the scaffold and valve selfexpand to the normal configuration in which the scaffold is engaged withthe pre-deployed host stent 140. In some arrangements the scaffold maybe of an expensile material which is expanded by an expander such as aballoon or the like.

Referring to FIGS. 47 to 50 there is illustrated another valve device151 according to the invention which is similar to that described aboveand like parts are assigned the same reference numerals. In this casethe valve 1 is housed within a support structure or scaffold 102 and isplaced into the lumen of a stent 140 as illustrated in FIGS. 51 to 53.The support structure may comprise a relatively short length (typically40 mm) of a mesh made from a shape memory material such as Nitinol. Themesh may be formed by laser cutting and/or may be of woven construction.Deployment into the lumen of the host stent 140 is via self expansionfrom a radially collapsed state within a delivery catheter 130 as shownin FIGS. 49 and 50. The device 151 is held in place within the stent 140by means of specific interaction mechanisms that increase the axialfriction of the support structure 102. FIGS. 51 to 53 illustrate theinteraction with the host stent 140. In this embodiment the supportstructure 102 has a series of loops or protrusions 155 extendingperpendicularly from its surface. These protrusions 155 engage with thestructure of any host stent 140 by interlocking with the existing meshas shown in FIGS. 52 and 53. The apical tip of each protrusion 155 is inthis case rounded or designed so as to be non-traumatic to any tissuethat may come into contact with the protrusion 155. The intrinsic radialforce of the support structure 102 as well as the flexural strength ofthe protrusions 155 interact to effect the retention performance of thesupport structure 102. Thus the stiffness or flexural strength of theprotrusion 155 and the radial force of the support structure 102 may bemodified to change the interlocking capability and retention performanceof the device.

The valve device 151 is also readily radially collapsible by distal andproximal drawstrings 170, 171. The distal drawstring 170 passes througheyelets 172 mounted to the support structure 102 at the distal end ofthe valve device 151. The distal drawstring 170 has an accessible pullstring 173 which, on pulling, pulls the drawstring 171 inwardly and thusreduces the diameter of the distal end of the support structure 102.Similarly the proximal drawstring 171 passes through eyelets 175 mountedthe support structure 102 at the proximal end of valve device 151. Theproximal drawstring 171 has an accessible pull string 177 which, onpulling, pulls the drawstring 171 inwardly and thus reduces the diameterof the proximal end of the support structure 102. The pull strings 173,177 can be readily gripped using a suitable instrument such as a grasperto draw the proximal and distal ends of the support structure 102inwardly for ease of removal of the valve device 151.

Referring to FIGS. 54 to 63 there is illustrated another valve device200 according to the invention which is similar to that described aboveand like parts are assigned the same reference numerals. In this casethe valve 1 is housed within a support structure or scaffold 102 and isplaced into the lumen of a stent 140 as illustrated in FIGS. 59 to 62.The support structure 102 may comprise a relatively short length(typically 40 mm) of a mesh made from a shape memory material such asNitinol. The mesh may be formed by laser cutting and/or may be of wovenconstruction. Deployment into the lumen of the host stent 140 is viaself expansion from a radially collapsed state within a deliverycatheter 130 as shown in FIGS. 56 to 61. The device 200 is held in placewithin the stent 140 by means of specific interaction mechanisms thatincrease the axial friction of the support structure 102. FIG. 62illustrates the interaction with the host stent 140. In this embodimentthe support structure 102 has a series of loops or protrusions 155extending perpendicularly from its surface. These protrusions 155 engagewith the structure of any host stent 140 by interlocking with theexisting mesh as shown in FIG. 62. The apical tip of each protrusion 155is in this case rounded or designed so as to be non-traumatic to anytissue that may come into contact with the protrusion 155. The intrinsicradial force of the support structure 102 as well as the flexuralstrength of the protrusions 155 interact to effect the retentionperformance of the support structure 102. Thus the stiffness or flexuralstrength of the protrusion 155 and the radial force of the supportstructure 102 may be modified to change the interlocking capability andretention performance of the device.

The valve device 200 is also readily radially collapsible by distal andproximal drawstrings 170, 171. The distal drawstring 170 passes througheyelets 172 mounted to the support structure 102 at the distal end ofthe valve device 200. The distal drawstring 170 has an accessible pullstring 173 which, on pulling, pulls the drawstring 171 inwardly and thusreduces the diameter of the distal end of the support structure 102.Similarly the proximal drawstring 171 passes through eyelets 175 mountedthe support structure 102 at the proximal end of valve device 200. Theproximal drawstring 171 has an accessible pull string 177 which, onpulling, pulls the drawstring 171 inwardly and thus reduces the diameterof the proximal end of the support structure 102. The pull strings 173,177 can be readily gripped using a suitable instrument such as a grasperto draw the proximal and distal ends of the support structure 102inwardly for ease of removal of the valve device 200.

It will be noted that in the case of this device 200 the diameter of thesupport scaffold is relatively uniform and the proximal and distal ends201, 202 of the device 200 are not tapered. We have found that theinterengagement of the rounded protrusions 155 in interstices defined inthe mesh structure of the stent 140 is sufficient to retain the device200 in position in the stent 140. Typically, the diameter of theexpanded support structure 102 will be slightly larger, for example 1 to5% larger than that of the host stent 140 at the desired deploymentlocation to assist in maintaining the scaffold 102 in situ.

In some cases, as illustrated in FIG. 63 the devices of the inventionsuch as the device 200 may be a radially collapsed state if it isdescribed to re-position the valve device 200 with the stent 140 or towithdraw the device 200, for example for replacement and/or forreplacement of the host stent 140.

Thus, the collapsibility of the valves enables its optional removal bydisengagement of the protrusions 155 from the host stent 140, thuseliminating any axial friction associated with the host stent 140.

The valve of FIGS. 1 to 63 is partially useful in patients with aconstriction in their esophagus, for example as a result of esophagealcancer. The valve may be located proximal to the distal end of theesophagus and proximal of the distal end of the prosthesis in which itis mounted/deployed. The valve is relatively short and is typically lessthan 30 mm, less than 25 mm, less than 20 mm, less than 15 mm and istypically about 10.6 mm long with an outer rim diameter of 18 mm orabout 11 mm long for an outer rim diameter of 20 mm.

The valve may have any desired number of leaflets, for example the valve250 illustrated in FIGS. 64 to 70 has six valve leaflets 251. Theseleaflets 251 are oriented perpendicular to direction of food flow toadditionally allow greater distensibility of the valve aperture.

Referring to FIGS. 71 to 83 there is illustrated another valve deviceaccording to the invention. The device 300 comprises an esophageal valve301 which can open automatically in the antegrade direction (foodintake) and in the retrograde direction (from the stomach to the mouth).

The valve 301 is similar to the valve of FIGS. 64 to 70 and comprises apolymeric valve body having a proximal outer support region with a rim302, six valve leaflets 303, and a main body region 306 extendingbetween the support rim 302 and the valve leaflets 303. The valveleaflets 303 extend inwardly and distally and terminate at distal endfaces 303 respectively. The leaflets each 303 have legs which extend atan included angle of 60° to each other. The adjacent pairs of legsco-apt to close the gap between the valve leaflets 303 when the valve isin the normally closed configuration.

The valve 301 has three configurations. The first configuration is anormally closed configuration in which the valve leaflets 303 co-apt toclose the valve. The second configuration is an antegrade openconfiguration in which the valve leaflets 303 are opened such that theleaflet leg pairs are opened and spaced-apart in response to anantegrade force F1 to allow flow through the valve 301. The thirdconfiguration is a retrograde open configuration in response to aretrograde force which is substantially larger than the antegrade forceF2.

The various configurations of the valve 1 are illustrated in FIGS. 71 to82. In the first or normally closed configuration (FIGS. 71, 72) thevalve leaflets 303 co-apt. When an antegrade force F1 is applied to thevalve leaflets 303 the leaflet legs pairs open to allow antegrade flowto pass (FIGS. 74, 77, 78). When the antegrade force F1 is removed theleaflets 303 return to the closed position under the inherent biasing ofthe polymeric material of the valve body (FIG. 71).

When a retrograde force F2 is applied to the valve body. This forceinitially pushes the valve leaflets 303 against one another (FIG. 80)and if the pressure is greater than a set value, the valve body willinvert as illustrated in FIG. 81. When the valve is fully opened inresponse to retrograde force F₂ the valve main body (and the leaflets303) extend proximally (upwardly) as illustrated in FIG. 81. This allowsretrograde flow to pass through the valve. When the retrograde force F2is removed the valve main body will return to the original configurationby everting in response to the biasing of the polymeric material toreturn to the normally closed configuration with the valve leafletsextending distally as illustrated in FIG. 71.

The valve leaflets 303 are reinforced in the region of co-aption. Inthis case, this is achieved by a local thickening of the polymericmaterial in this region. Similarly the support rim 302 is reinforced bya local thickening of the polymeric material.

The region of co-aption of the valve leaflets 303 has an axial extentwhich is typically from 1 to 5 mm. This ensures positive co-aption ofthe leaflets across a significant interfacial area when the valve is inthe normally closed configuration. The thickness of the leaflets at theregion of co-aption is typically between 0.1 mm and 10 mm.

The valve body 306 has a generally concave outer face and a generallyconvex inner face.

The valve 300 is a two-way valve. Different forces are required to openthe valve from the proximal or distal directions. The valve 300 requiresvery little force to open in the antegrade direction, a pressure of 0.7mm Hg in the antegrade direction is sufficient to allow a flowrate of140 ml/min. In the retrograde direction the valve 1 can hold pressuresof between 15 mmHg and 40 mmHg and higher. By varying the properties(such as density) of the material of the valve the valve can be tailoredto accommodate varying yield pressures. The valve 300 accomplishes thisby controllably inverting when placed under pressure in the retrogradedirection.

The valve 300 of the invention returns to its original working positionafter being fully opened in the retrograde direction. This isaccomplished without damaging the working valve.

When the valve 300 is opened by food passing in the antegrade directionthe leaflets 303 open. The outer face of the valve has a greaterresistance to change in shape and thus the force required to open mainbody in the retrograde direction is higher.

The important characteristics influencing the functioning of the valve300 are the leaflet legs that impinge on one another. By varying thegeometry and length of the leaflets 303 the valve 300 can be made toopen in the retrograde direction at different pressures. Opening in theantegrade direction is somewhat less dependant on the geometry of theleaflets and more dependant on the elasticity and density of thematerial the device is made from. Additionally, the overall diameter andthe diameter to which the leaflets open influence the opening force inboth directions.

Because the stomach tends to have a slightly higher pressure than theesophagus (on average. 12 mmHg), a closed valve will experience thispressure at its distal surface. This distal pressure can ammeliorate theclosing of a distally extending or tapering surface. However, previousexamples of valves in the literature have relied on smooth surfaces totake advantage of this gastric pressure differential. Thus the onlymeans of maximising the force generated by the gastric pressure was toincrease the length of the distally extending or tapering surface. Thisin turn gave rise to problems associated will elongate structuresbecoming blocked with antegrade food flow and retrograde flow. Thecurrent invention teaches a method of retaining the short length of thevalve structure and maximising the force generated by the gastricpressure through an increase in the surface area to length ratio. Thisis achieved by increasing the surface area of the distal surface of thevalve by introducing pleats or folds (leaflets).

The valve may be of any suitable biocompatible polymeric material. Itmay be of a biocompatible polymeric material having properties whichallow the valve to function as described.

The materials used for the production of this valve have a % elongationbetween 50% and 3000%. The material also has a tensile strength ofbetween 0.01 and 5 MPa. Addionally the material could have anantimicrobial action to prevent colonisation when in-vivo. Additionallythe material can be elastic or viscoelastic and can optionally be anopen cell foam. The density of the material should be between 0.1 g/cm3to 1.5 g/cm3.

The valve 300 of the invention may be mounted to any suitable luminalprosthesis, especially an esophageal prosthesis 350. The rim 302 of thevalve provides a mounting ring for mounting within the prosthesis, forexample, the valve 300 may be mounted to the stent by suturing the rim 2to the stent mesh using sutures 351 as illustrated particularly in FIG.71.

The prosthesis 350 may be of any suitable type. An uncoated andunsleeved stent 350 is illustrated in FIGS. 71 to 81.

In this case the valve 300 is mounted to a distal end of the prosthesis350. The stomach produces a pressure of 7 mm Hg. The distal end of thevalve is exposed to this pressure which compresses the material furtherto augment the closure force on the already closed valve. The prosthesis350 is located so that it can be readily anchored in place for example,by tissue anchors 361 in the gastric cardia—in the region of tissuebetween the entrance to the stomach and lower esophageal sphincter. Ingeneral, the tissue wall is thickened in this region which facilitatesanchoring of the prosthesis 350. The tissue anchors may be such as thoseused in the commercially available G-Cath system from USGI.

The prosthesis 350 is designed to be in situ for a long period of time.With a standard Nitinol metal stent a patient may be aware of itspresence because of the radial force applied by the stent. Theprosthesis 350 in contrast can be of a braided plastic mesh which issufficiently self expanding that it remains in situ during fixing forexample, using the tissue anchors 361. The mesh of the stent should beopen enough to accept the tissue anchor without damaging the mesh butdense enough to prevent pull-through of the tissue anchor. Theprosthesis typically has a radial force of less than 1.9 Kpa to retainit in situ without causing discomfort to the patient.

The valve device according to this embodiment is especially useful inthe treatment of GERD. The valve is located distal to the distal end ofthe esophagus.

It will be noted that the valve is relatively short and does not extendsignificantly into the stomach. Prior art “windsock” type devices arelong which can result in clogging by the contents of the stomach.Further material can rise up from the stomach by capillary action insuch windsock devices. In contrast the GERD valve of the invention istypically less than 50 mm, less than 40 mm, less than 30 mm and istypically about 23 mm long for a diameter of 23 mm.

Referring to FIGS. 83 and 84 there is illustrated another device 400according to the invention which is similar to the device of FIGS. 71 to82 and like parts are assigned the same reference numerals. In this casethe valve 301 is mounted to the prosthesis 350 by overmoulding 401 ofthe rim 302 of the valve to the distal end of the prosthesis 350.Overmoulding assists in spreading the axial load as there is a largearea of content between the prosthesis 350 and the valve rim 302.

The esophageal valves of the invention can open automatically in theantegrade direction (food intake) and in the retrograde direction (fromthe stomach to the mouth).

The valves are two-way valves. Different forces are required to open inthe valve from the proximal or distal directions. The valves requirevery little pressure to open in the antigrade direction, water at apressure as low as 0.7 mmHg will allow a flowrate of at least 140ml/min. In the retrograde direction the valve can hold pressures of 30mmHg and higher. By varying the properties (such as density) of thematerial of the valve, the valve can be tailored to accommodate varyingyield pressures. The valve accomplishes this by controllably invertingwhen placed under pressure in the retrograde direction.

The valves of the invention returns to its original working positionafter being fully opened in the retrograde direction. This isaccomplished without damaging the working valve.

It will be appreciated that whilst the invention has been described withreference to an esophageal valve for mounting to a pre-deployedesophageal stent it may also be applied to mounting of valves in otherbody passageways including any artery or the urethra, or other locationsin the gastrointestinal system such as a replacement for the ileocecalvalve located between the small and the large intestine.

The following section describes one group of biomaterials that aresuitable for manufacturing a valve of the invention.

Use of polyethers as soft segments in polyurethane foams is know toresult in soft elastic and viscoelastic materials due to the dynamicreinforcing effect of hydrogen bonding. Conversely, use of non-hydrogenbonding hydrophobic soft segments results in harder, less elasticmaterial. Blending of such hydrophobic and hydrophilic homopolymer softsegments as shown in FIG. 85 via urethane/urea linkages is known in theart to achieve mechanical properties appropriate to specificapplications.

Acid catalysed hydrolytic degradation occurs at urethane linkages withinpolyurethane materials. These urethane/urea linkages are therefore the‘weak-links’ of the polyurethane material. It follows that the intrinsichydrophilicity of the polyurethane material will affect the rate ofhydrolysis through modulation of water uptake. Thus, such materials areincompatible with use in a gastric environment (i.e., a highly acidicaqueous environment).

Thus, in some embodiments, the present invention provides a multiblockcopolymer that is biomimetic and hydrolytically stable in a gastricenvironment. Such multiblock copolymers are of formula I:

wherein:

each

represents a point of attachment to a urethane or urea linkage;

each of X and Y is independently a polymer or co-polymer chain formedfrom one or more of a polyether, a polyester, a polycarbonate, or afluoropolymer;

each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from one ormore of R, OR, —CO₂R, a fluorinated hydrocarbon, a polyether, apolyester or a fluoropolymer;

each R is independently hydrogen, an optionally substituted C₁₋₂₀aliphatic group, or an optionally substituted group selected fromphenyl, 8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m n and p is independently 2 to 100; and

each of L¹ and L² is independently a bivalent C₁₋₂₀ hydrocarbon chainwherein 1-4 methylene units of the hydrocarbon chain are optionally andindependently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—, —OC(O)—, —C(O)O—, or a bivalentcycloalkylene, arylene, heterocyclene, or heteroarylene, provided thatneither of L¹ nor L² comprises a urea or urethane moiety.

2. Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. In someembodiments, aliphatic groups contain 1-10 carbon atoms. In otherembodiments, aliphatic groups contain 1-8 carbon atoms. In still otherembodiments, aliphatic groups contain 1-6 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-4 carbon atoms. Suitablealiphatic groups include, but are not limited to, linear or branched,alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ [or C₁₋₆] saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n), wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring”.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘); —NO₂; —CN;—N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(∘), taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, which may be substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

3. Description of Exemplary Embodiments

A. Multiblock Copolymers

As described generally above, one embodiment of the present inventionprovides a triblock copolymer of formula I:

wherein the copolymers are chemically interspersed (bound) betweenurethane and/or urea linkages (i.e., at the bond designated with

) and wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and R⁶is as defined and described herein.

As defined generally above, the each of X and Y groups of formula I isindependently a polymer or co-polymer chain formed from one or more of apolyether, a polyester, a polycarbonate, and a fluoropolymer.

Examples of polymer or co-polymer chains represented by X and/or Yinclude: poly(ethylene oxide), poly(difluoromethyl ethylene oxide),poly(trifluoromethyl ethylene oxide), poly(propylene oxide),poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof, poly(dimethylsiloxane), poly(diethylsiloxane) andhigher alkyl siloxanes, poly(methyl phenyl siloxane), poly(diphenylsiloxane), poly(methyl di-fluoroethyl siloxane), poly(methyltri-fluoroethyl siloxane), poly(phenyl di-fluoroethyl siloxane),poly(phenyl tri-fluoroethyl siloxane) and copolymers thereof,poly(ethylene terephthalate) (PET), poly(ethylene terephthalate ionomer)(PETI), poly(ethylene naphthalate) (PEN), poly(methylene naphthalate)(PTN), poly(butylene teraphalate) (PBT), poly(butylene naphthalate)(PBN), polycarbonate. In certain embodiments, the present inventionprovides a pre-formed soft segment for a polyurethane/urea foam.

In some embodiments X is a polyether and Y is a polyether. Morespecifically in one case X and Y are both poly(propylene oxide).

In certain embodiments, m and p are each independently between 2 and 50and n is between 2 and 20. In some embodiments, m and p are eachindependently between 2 and 30 and n is between 2 and 20.

As defined generally above, each of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently selected from one or more of R, OR, —CO₂R, a fluorinatedhydrocarbon, a polyether, a polyester or a fluoropolymer. In someembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is —CO₂R. In someembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is —CO₂R whereineach R is independently an optionally substituted C₁₋₆ aliphatic group.In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is—CO₂R wherein each R is independently an unsubstituted C₁₋₆ alkyl group.Exemplary such groups include methanoic or ethanoic acid as well asmethacrylic acid and other acrylic acids.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently R. In some embodiments, one or more of R¹, R², R³, R⁴, R⁵and R⁶ is an optionally substituted C₁₋₆ aliphatic group. In certainembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is an optionallysubstituted C₁₋₆ alkyl. In other embodiments, one or more of R¹, R², R³,R⁴, R⁵ and R⁶ is an optionally substituted group selected from phenyl,8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, orsulphur. Exemplary such R¹, R², R³, R⁴, R⁵ and R⁶ groups include methyl,ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl,phenyl, pyridyl, morpholinyl, pyrrolidinyl, imidazolyl, and cyclohexyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently —OR. In some embodiments, one or more of R¹, R², R³, R⁴,R⁵ and R⁶ is —OR wherein R is an optionally substituted C₁₋₆ aliphaticgroup. In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶is —OR wherein R is C₁₋₆ alkyl. In other embodiments, one or more of R¹,R², R³, R⁴, R⁵ and R⁶ is —OR wherein R is an optionally substitutedgroup selected from phenyl, 8-10 membered bicyclic aryl, a 4-8 memberedmonocyclic saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, orsulphur, or 5-6 membered monocyclic or 8-10 membered bicyclic heteroarylgroup having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulphur. Exemplary such R¹, R², R³, R⁴, R⁵ and R⁶ groupsinclude —Omethyl, —Oethyl, —Opropyl, —Oisopropyl, —Ocyclopropyl,—Obutyl, —Oisobutyl, —Ocyclobutyl, —Ophenyl, —Opyridyl, —Omorpholinyl,—Opyrrolidinyl, —Oimidazolyl, and —Ocyclohexyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently R wherein each R is a C₁₋₆ aliphatic group substitutedwith one or more halogens. In some embodiments, each R is C₁₋₆ aliphaticsubstituted with one, two, or three halogens. In other embodiments, eachR is a perfluorinated C₁₋₆ aliphatic group. Examples of fluorinatedhydrocarbons represented by R¹, R², R³, R⁴, R⁵ and R⁶ include mono-,di-, tri, or perfluorinated methyl, ethyl, propyl, butyl, or phenyl. Insome embodiments, each of R¹, R², R³, R⁴, R⁵ and R⁶ is trifluoromethyl,trifluoroethyl, or trifluoropropyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a polyether. Examples of polyethers represented by R¹, R²,R³, R⁴, R⁵ and R⁶ include poly(ethylene oxide), poly(difluoromethylethylene oxide), poly(trifluoromethyl ethylene oxide), poly(propyleneoxide), poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a polyester. Examples of polyesters represented by R¹, R²,R³, R⁴, R⁵ and R⁶ include poly(ethylene terephthalate) (PET),poly(ethylene terephthalate ionomer) (PETI), poly(ethylene naphthalate)(PEN), poly(methylene naphthalate) (PTN), poly(butylene teraphalate)(PBT), poly(butylene naphthalate) (PBN), polycarbonate.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a fluoropolymer. Examples of fluoropolymers represented byR¹, R², R³, R⁴, R⁵ and R⁶ include poly(tetrafluoroethylene), poly(methyldi-fluoroethyl siloxane), poly(methyl tri-fluoroethyl siloxane),poly(phenyl di-fluoroethyl siloxane).

In some embodiments, R¹, R², R³, R⁴, R⁵ and R⁶ is independentlyhydrogen, hydroxyl, carboxylic acids such as methanoic or ethanoic acidas well as methacrylic acid and other acrylic acids. Alkyl or arylhydrocarbons such as methyl, ethyl, propyl, butyl, phenyl and ethersthereof. Fluorinated hydrocarbons such as mono-, di-, tri, orperfluorinated methyl, ethyl, propyl, butyl, phenyl. Polyether such asPoly(ethylene oxide), poly(difluoromethyl ethylene oxide),poly(trifluoromethyl ethylene oxide), poly(propylene oxide),poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof. Polyesters such as Poly(ethylene terephthalate)(PET), poly(ethylene terephthalate ionomer) (PETI), poly(ethylenenaphthalate) (PEN), poly(methylene naphthalate) (PTN), Poly(ButyleneTeraphalate) (PBT), poly(butylene naphthalate) (PBN), polycarbonate andfluoropolymer such as Poly(tetrafluoroethylene), poly(methyldi-fluoroethyl siloxane), poly(methyl tri-fluoroethyl siloxane),poly(phenyl di-fluoroethyl siloxane).

In some embodiments, m and p are between 2 and 50 and n is between 2 and20. In certain embodiments, m and o are between 2 and 30 and n isbetween 2 and 20.

As defined generally above, each of L¹ and L² is independently abivalent C₁₋₂₀ hydrocarbon chain wherein 1-4 methylene units of thehydrocarbon chain are optionally and independently replaced by —O—, —S—,—N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—,—OC(O)—, —C(O)O—, or a bivalent cycloalkylene, arylene, heterocyclene,or heteroarylene, provided that neither of L¹ nor L² comprises a urea orurethane moiety. In some embodiments, each of L¹ and L² is independentlya bivalent C₁₋₂₀ alkylene chain. In certain embodiments, each of L¹ andL² is independently a bivalent C₁₋₁₀ alkylene chain. In certainembodiments, each of L¹ and L² is independently a bivalent C₁₋₆ alkylenechain. In certain embodiments, each of L¹ and L² is independently abivalent C₁₋₄ alkylene chain. Exemplary such L¹ and L² groups includemethylene, ethylene, propylene, butylene or higher bivalent alkanes.

In some embodiments, each of L¹ and L² is independently a bivalent C₁₋₂₀alkylene chain wherein one methylene unit of the chain is replaced by—O—. In some embodiments, each of L¹ and L² is independently a bivalentC₁₋₁₀ alkylene chain wherein one methylene unit of the chain is replacedby —O—. In some embodiments, each of L¹ and L² is independently abivalent C₁₋₆ alkylene chain wherein one methylene unit of the chain isreplaced by —O—. In some embodiments, each of L¹ and L² is independentlya bivalent C₁₋₄ alkylene chain wherein one methylene unit of the chainis replaced by —O—. Exemplary such L¹ and L² groups include —OCH₂—,—OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂CH₂CH₂CH₂—, or higher bivalent alkyleneethers.

In some embodiments, each of L¹ and L² is independently a bivalent C₁₋₂₀alkylene chain wherein at least one methylene unit of the chain isreplaced by —O— and at least one methylene unit of the chain is replacedby a bivalent arylene. In some embodiments, each of L¹ and L² isindependently a bivalent C₁₋₁₀ alkylene chain wherein at least onemethylene unit of the chain is replaced by —O— and at least onemethylene unit of the chain is replaced by a bivalent arylene. In someembodiments, each of L¹ and L² is independently a bivalent C₁₋₆ alkylenechain wherein at least one methylene unit of the chain is replaced by—O— and at least one methylene unit of the chain is replaced by abivalent arylene. In some embodiments, each of L¹ and L² isindependently a bivalent C₁₋₄ alkylene chain wherein at least onemethylene unit of the chain is replaced by —O— and at least onemethylene unit of the chain is replaced by a bivalent arylene. Exemplarysuch L¹ and L² groups include —OCH₂-phenylene-, —OCH₂CH₂-phenylene-,—OCH₂CH₂-phenylene-CH₂—, —OCH₂CH₂CH₂CH₂-phenylene-, and the like.

One of ordinary skill in the art would understand that a polyurethaneresults from the reaction of a diisocyanate and a hydroxyl group.Similarly, a polyurea results from the reaction of a diisocyanate and anamine. Each of these reactions is depicted below.

Thus, it is readily apparent that provided compounds of formula I can befunctionalized with end groups suitable for forming urethane and/or urealinkages. In certain embodiments, the present invention provides acompound of formula II:

wherein:

each of R^(x) and R^(y) is independently —OH, —NH₂, a protected hydroxylor a protected amine;

each of X and Y is independently a polymer or co-polymer chain formedfrom one or more of a polyether, a polyester, a polycarbonate, and afluoropolymer;

each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from one ormore of R, OR, —CO₂R, a fluorinated hydrocarbon, a polyether, apolyester or a fluoropolymer;

each R is independently hydrogen, an optionally substituted C₁₋₂₀aliphatic group, or an optionally substituted group selected fromphenyl, 8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m n and p is independently 2 to 100; and

each of L¹ and L² is independently a bivalent C₁₋₂₀ hydrocarbon chainwherein 1-4 methylene units of the hydrocarbon chain are optionally andindependently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—, —OC(O)—, —C(O)O—, or a bivalentcycloalkylene, arylene, heterocyclene, or heteroarylene, provided thatneither of L¹ nor L² comprises a urea or urethane moiety.

In some embodiments, each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵,and R⁶ is as defined and described herein.

As defined generally above, each of R^(x) and R^(y) is independently—OH, —NH₂, a protected hydroxyl or a protected amine. In someembodiments, both of R^(x) and R^(y) are —OH. In other embodiments, bothof R^(x) and R^(y) are —NH₂. In some embodiments one of R^(x) and R^(y)is —OH and the other is —NH₂.

In some embodiments, each of R^(x) and R^(y) is independently aprotected hydroxyl or a protected amine. Such protected hydroxyl andprotected amine groups are well known to one of skill in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley &Sons, 1999, the entirety of which is incorporated herein by reference.Exemplary protected amines include methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate,formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys),p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Exemplary hydroxyl protecting groups include methyl, methoxylmethyl(MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec),2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate,alkyl vinyl carbonate alkyl allyl carbonate, alkyl p-nitrophenylcarbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate,alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate,alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts). For protecting 1,2- or 1,3-diols, the protecting groups includemethylene acetal, ethylidene acetal, 1-t-butylethylidene ketal,1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal,2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal,p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal,3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal,methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethyleneortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine orthoester, 1,2-dimethoxyethylidene ortho ester, α-methoxybenzylidene orthoester, 1-(N,N-dimethylamino)ethylidene derivative,α-(N,N′-dimethylamino)benzylidene derivative, 2-oxacyclopentylideneortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

One of ordinary skill in the art will appreciate that the choice ofhydroxyl and amine protecting groups can be such that these groups areremoved at the same time (e.g., when both protecting groups are acidlabile or base labile). Alternatively, such groups can be removed in astep-wise fashion (e.g., when one protecting group is removed first byone set of removal conditions and the other protecting group is removedsecond by a different set of removal conditions). Such methods arereadily understood by one of ordinary skill in the art.

In certain embodiments, the present invention provides a compound of anyof formulae II-a, II-b, II-c, and II-d:

wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and R⁶ is asdefined and described herein.

Exemplary triblock copolymers of the present invention are set forthbelow:

wherein each of m, n, and p is as defined and described herein.

In some embodiments, the present invention provides a polymer foam,comprising:

-   -   (a) one or more triblock copolymers of formula I:

-   -   wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and        R⁶ is as defined and described herein; and    -   (b) wherein the copolymers are chemically interspersed (bound)        between urethane and/or urea linkages (i.e., at the bond        designated with        ).

The invention further provides a pre-formed soft segment of the formulaI as defined above. In some embodiments, the present invention providesa polyurethane/urea foam comprising a soft segment triblock copolymer offormula I.

In some embodiments, the present invention provides a viscoelasticbiostable water blown foam, comprising:

-   -   (a) one or more triblock copolymers of formula I:

-   -   wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and        R⁶ is as defined and described herein; and    -   (b) wherein the copolymers are chemically interspersed (bound)        between urethane and/or urea linkages (i.e., at the bond        designated with        ).

It has been surprisingly found that polyurethanes and/or polyureascomprising a triblock copolymer of the present invention are stable togastric fluid. Such polyurethanes and polyureas prepared using triblockcopolymers of the present invention are viscoelastic and stable togastric fluid. In some embodiments, a provided viscoelastic material isa foam.

In certain embodiments, a provided biostable foam is stable to gastricfluid. In some embodiments, a provided biostable foam is stable togastric fluid for at least one year. In some embodiments, a providedbiostable foam is stable to gastric fluid for at least 3 months, for atleast 4 months, for at least 5 months, for at least 6 months, for atleast 7 months, for at least 8 months, for at least 9 months, for atleast 10 months, for at least 11 months, or for at least one year.Methods for determining stability of a provided biostable foam are knownin the art utilizing simulated gastric fluid and include those describedin detail in the Exemplification, infra.

In some embodiments, a provided viscoelastic foam, comprising a triblockcopolymer of the present invention, is characterized in that the foamtakes up less than about 30% by weight of water at equilibrium. Incertain embodiments, a provided viscoelastic foam takes up less thanabout 5%, less than about 10%, less than about 15%, less than about 20%,less than about 25%, or less than about 30% by weight of water atequilibrium. One of ordinary skill in the art will appreciate that suchchemical stability (i.e., in gastric fluid and therefore at very low pH)and hyrophobicity (i.e., water uptake of less than about 30% by weight)are characterisitics that differ dramatically from known siloxanepolymers that are utilized in, e.g., the manufacture of contact lenses.For example, siloxane polymer that are utilized in, e.g., themanufacture of contact lenses require a water uptake of 50-120%.

As described above, the present invention provides a viscoelastic foamcomprising a triblock copolymer of the present invention. It wassurprisingly found that a provided foam has a high elongation capacityand the ability to recover very slowly following elongation. Indeed, itwas found that a provided viscoelastic foam has an elongation capacityof about 200-1200%. In some embodiments, a provided viscoelastic foamhas an elongation capacity of about 500%.

In some embodiments, a provided viscoelastic foam has a tensile strengthof about 0.1 to about 1.0 MPa. In certain embodiments, a providedviscoelastic foam has a tensile strength of about 0.25 to about 0.5 MPa.

In some embodiments, a provided viscoelastic foam has a Young's Modulusof about 0.1 to about 0.6 MPa. In certain embodiments, a providedviscoelastic foam has a Young's Modulus of about 0.1 to about 0.5 MPa.

One of ordinary skill in the art will appreciate that, depending uponthe physical characteristics required for a particular use of a providedfoam, a foam of varying densities can be prepared. For example, a valvehaving a thinner wall would require a foam having a higher density thana similar valve having a thicker wall in order to result in each valvehaving a similar physical characteristic (e.g., tensile strength, andthe like). Thus, in certain embodiments, a provided viscoelastic foamhas a density of 0.1 to 1.5 g/cm³. In certain embodiments, a providedviscoelastic foam has a density of 0.3 to 1.2 g/cm³. In certainembodiments, a provided viscoelastic foam has a density of 0.8 to 0.9g/cm³. In some embodiments, a provided viscoelastic foam has a densityof 0.5 to 0.6 g/cm³.

In certain embodiments, the present invention providespolyether-siloxane and polyether-fluorosiloxane polyurethane materialswith a greatly reduced number of weak-links as illustrated by FIG. 86and FIG. 87. This was achieved by preforming the soft segment prior tothe polyurethane reaction. In the examples below a triblock copolymerbased on polydimethyl siloxane and polypropylene oxide was used but itwill be appreciated that other triblock copolymers such as those formedfrom polysiloxanes and poly(ethylene oxide), poly(difluoromethylethylene oxide), poly(trifluoromethyl ethylene oxide), poly(propyleneoxide), poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof, poly(dimethylsiloxane), poly(diethylsiloxane) andhigher alkyl siloxanes, poly(methyl phenyl siloxane), poly(diphenylsiloxane), poly(methyl di-fluoroethyl siloxane), poly(methyltri-fluoroethyl siloxane), poly(phenyl di-fluoroethyl siloxane),poly(phenyl tri-fluoroethyl siloxane) and copolymers thereof,poly(ethylene terephthalate) (PET), poly(ethylene terephthalate ionomer)(PETI), poly(ethylene naphthalate) (PEN), poly(methylene naphthalate)(PTN), poly(butylene teraphalate) (PBT), poly(butylene naphthalate)(PBN) and polycarbonate could be used.

Referring to FIG. 86, copolymers of the form ABA, ABC and BAB wereproduced from homopolymers of polysiloxane and polypropylene oxide whichwere covalently linked using bonds less labile than urethane/urea. Themolecular weight and chemical charateristics of such homopolymers weretailored to achieve a pre-soft-segment with the appropriate balance ofhydrophilicity/hydrophobicity. Without wishing to be bound by anyparticular theory, it is believe that by using a non-urethane linkedtri-block copolymer instead of the constituent homopolymers as softsegments that the mechanical characteristics and hydrolytic stability ofthe resulting material is substantially improved.

In some embodiments, the present invention provides a foam comprising acopolymer of the present invention. Such foams offer specific advantagesover solid elastomers, especially for gastrointestinal deviceapplications. These advantages include enhanced biostability in thegastric environment, compressibility, viscoelasticity and high ‘surfacearea to volume ratio’. The foam formulations of the invention can mimicmechanical characteristics of the native gastrointestinal tissue.

A biostable water blown foam was prepared from heterogenous reagents.

The prior art describes polyurethane foams that are prepared by thesequential reaction of polymer chains to one another resulting in a highmolecular weight solid material. In all cases the polymeric precursorsdescribed in the art are linked together by urethane/urea linkages asillustrated in FIG. 85. However, each urethane/urea linkage is apossible site for degradation.

In the invention we have prepared a biostable polyurethane/urea foamwith much fewer ‘weak links’ by using co-polymer precursors as shown inFIG. 86.

Polyurethane reactions have historically been carried out in a singlephase due to ease of processing. However, we have made novel materialsby combining physically heterogenous reaction pre-cursors together toform a stable two-phase dispersion (‘water-in-oil’) which was thenreacted to form a foam.

Exemplification

In two specific examples X and Y are both polyethers namelypolypropylene oxide) (PPO). These were formulated into copolymers withpoly(dimethylsiloxane) (PDMS) and poly(trifluoropropyl methylsiloxane)respectively in varying ratios as described by the following formulae:

The formulations contained a number of other components including:

Branching Agent—DEOA

Diethanolamine (DEOA) is used as a branching agent although it issometimes known as a crosslinking agent. The molecular weight of DEOA is105.14 g/mol. The effect of the DEOA is to influence softness andelasticity of the end polymer.

Gelling Catalyst—Bismuth Neodecanoate (BICAT)

Bismuth neodecanoate is supplied as BiCat 8108M from Shepherd. It has amolecular weight of 722.75 g/mol. This catalyst is used to facilitatethe complete reaction between isocyanate and hydroyl or amine functionalgroups.

Blowing Catalyst—DABCO 33-lv

DABCO is a common blowing catalyst for reaction between NCO and H₂O. Ithas a molecular weight of 112.17 g/mol. This catalyst has the effect, incombination with H₂O, of manipulating the foam rise characteristics.

Example 1

Synthesis of Aliphatic Linked Fluorosiloxane Based Triblock CopolymerPre-Soft-Segment:

This is a 2 step process. In the first step silanol terminatedpoly(trifluoropropyl methyl siloxane) is converted into its dihydridederivative. In the next step, this dihydride derivative is reacted withthe allyl terminated poly(propylene glycol).

The synthetic procedure is as follows:

Step 1:

To a 4 neck separable flask fitted with mechanical stirrer, was added 40g of Silanol terminated poly(trifluoropropyl methylsiloxane) (FMS-9922from Gelest Inc.) and this was mixed with 50 ml of toluene and fittedwith a continuous flush of Nitrogen. To the reaction mixture 7.57 g ofdimethyl chlorosilane (DMCS, from Sigma Aldrich) was added slowly overabout 20 minutes keeping the temperature of the mixture constant at 30°C. With each addition of dimethyl chlorosilane, the mixture became hazybut cleared in a short period of time. Once the addition of dimethylchlorosilane was complete, the mixture was heated to 90° C. for 3 hours.The reaction was then washed with excess water several times to reducethe acidity of the mixture. The resulting mixture was dried over silicagel, filtered and vacuumed to remove solvent and traces of water at 65°C. overnight. A clear fluid was then obtained with a very strong Si—Hband in infra red spectroscopy (IR) at 2130 cm⁻¹, which confirms thereaction. GPC analysis showed the molecular weight to be 1200 g/mol.

Step 2:

To 90 ml of reagent grade toluene in a 4 neck separable flask fittedwith mechanical stirrer, 46.67 g of Allyl terminated poly(propyleneglycol) (MW=700 g/mol, Jiangsu GPRO Group Co.) was added and then heatedto reflux. Then 40 g of Hydride terminated FMS-9922 was dissolved in 50ml of reagent grade toluene and the temperature raised to around 90° C.To the reaction mixture 2 drops of hexachloroplatinic(IV) acid (0.01MH₂PtCl₆ from Sigma) solution in isopropanol (by Merck) was then added.After this catalyst solution had been added, the mixture was refluxedfor 1 hour and the solvent distilled off in order to get the finalproduct. The reaction was followed by H-NMR and gel permeationchromatography (GPC) confirmed the final molecular weight to be 2700g/mol.

TABLE 1 Resulting polymer block ratios Stoiciometric ratios for reactionproduct: Polymer block PO F—SiO PO m n p Ratio 11 9.7 11

Example 2

Synthesis of Aliphatic Linked Dimethylsiloxane Based Triblock CopolymerPre-Soft-Segment:

To 130 ml of reagent grade toluene in a separable flask fitted with amechanical stirrer, was added 64 g of allyl terminated poly(propyleneglycol) (MW=700 g/mol, Jiangsu GPRO Co.) and both were mixed and heatedto reflux. Then 40 g of hydride terminated poly(dimethyl siloxane)(Silmer H Di 10 by Siltech Corp.) was dissolved in 50 ml reagent gradetoluene and the temperature raised to around 90° C. To this reactionmixture 2 drops of hexachloroplatinic(IV) acid (0.01M H₂PtCl₆ fromSigma) solution in isopropanol was added. After this catalyst solutionwas added, the mixture was refluxed for 1 hour and then the solvent wasdistilled off in order to get the final product. The reaction wasfollowed with H-NMR and gel permeation chromatography (GPC) confirmedthe final molecular weight of the product to be 2300 g/mol.

TABLE 2 Polymer block ratios Stoiciometric ratios for reaction product:Polymer block PO SiO PO m n p Ratio 11 11 11

Example 3

Synthesis of Aromatic Linked Siloxane Based Triblock CopolymerPre-Soft-Segment:

To a 100 ml separable flask fitted with a mechanical stirrer, 15 g ofhydroxy terminated polydimethyl siloxane (DMS-S14 from Gelest Inc.) wasadded along with 5.36 g of di-chloro p-xylene (from Sigma) and 0.0089 gof Copper(II) acetylacetonate (Cu(Acac)₂ from Sigma). The reactionmixture was refluxed at 110° C. for 5 hrs. At this point, 19.77 g ofhydroxy terminated poly(propylene glycol) (from Sigma) was addeddropwise and the reaction mixture was then refluxed for another 15 hr.The progress of reaction was followed by ¹H-NMR and the final molecularweight, determined by gel permeation chromatography (GPC), was 3000g/mol.

H-NMR analysis: Solvent used for ¹H-NMR analysis is CDCl₃.

Aromatic H=7.25-7.45 ppm, —CH₂=4.5-4.6 ppm, —CH₃ (of PPO)=1-1.4 ppm,—CH₂ (of PPO)=3.2-3.8 ppm, —OH (of PPO)=3.8-4 ppm, —CH₃(silanol)=0.5-0.8 ppm.

TABLE 3 Resulting polymer block ratios Stoiciometric ratios for reactionproduct: Polymer block PO SiO PO m n p Ratio 14 15.5 14

Example 4

Synthesis of Aromatic Linked Fluorosiloxane Based Triblock CopolymerPre-Soft-Segment:

To a 100 ml separable flask fitted with a mechanical stirrer, 15 g ofhydroxy terminated polytrifluoromethyl siloxane (FMS-9922, Gelest inc.)was added along with 5.9 g of di-chloro p-xylene and 0.0098 g ofcopper(II) acetylacetonate (Cu(Acac)₂ from Sigma). The reaction mixturewas refluxed at 110° C. for 5 hrs. At this point, 21.75 g of hydroxyterminated poly(propylene glycol) (from Sigma) was added dropwise to thereaction mixture. The reaction was refluxed for another 15 hr. Theprogress of reaction was followed by ¹H-NMR analysis and the molecularweight, determined by gel permeation chromatography (GPC), was 3100g/mol.

¹H-NMR analysis: Solvent used for H-NMR analysis is CDCl₃.

Aromatic ¹H=7.25-7.45 ppm, —CH₂=4.5-4.6 ppm, —CH₃ (of PPO)=1-1.4 ppm,—CH₂ (of PPO)=3.2-3.8 ppm, —OH (of PPO)=3.8-4 ppm, —CH₃(silanol)=0.5-0.8 ppm.

TABLE 4 Polymer block ratios Stoiciometric ratios for reaction product:Polymer block PO FSiO PO m n p Ratio 14 9.2 14

Example 5

Preparation of Water Blown Foam:

The pre-soft segments prepared can be described as having polymer blockratios which are numerically represented by the letters m, n and o forthe constituents PO/SiO/PO respectively. The triblock copolymersprepared in Examples 1 and 2 with specific m, n, o ratios wereformulated into polyurethane/urea foams as illustrated by Table 7.

The process for preparing the foam was a two-step procedure. Thefollowing describes the method of manufacture of the first product inTable 7. The same procedure was used to prepare other foams as describedby Table 8.

-   -   Step 1) Firstly a mixture was made with 0.041 g of DABCO LV-33        (Airproducts), 0.120 g of bismuth neodecanoate (Bicat 8108M from        Shepherd chemicals), 0.467 g of diethanol amine (DEOA, from        Sigma), 7.917 g of synthesized block copolymer, 0.200 g water        and 0.1 g of surfactant (Niax L-618 from Airproducts) in a        plastic flat bottomed container. This is then thoroughly mixed        manually for 30 sec until a homogenous mixture was obtained.    -   Step 2) To the above mixture, 15 g of a diisocyanate prepolymer        (PPT 95A Airproducts) was added. This was then thoroughly mixed        by a mechanical stirrer for about 5 seconds. The material was        then molded and cured at 70° C. for 2.5 hours and post cured at        50° C. for another 3 hours.

TABLE 5 Formulation details for foam Polymer Formulation block(PO/SiO/PO) Identification Ratio m:n:p DABCO BICAT DEOA H₂O VF230209A11:11:11 0.0325 0.015 0.40 1.0 VF090309B 11:9:11 0.0325 0.015 0.40 1.0

Example 6

Comparative Example of Formulation of Water Blown Foam from TriblockCopolymer Pre-Soft Segment and Individual Homopolymers:

Polyurethane/urea polymer foams from Example 5 were compared to foamsmade from the stoiciometric equivalent homopolymer soft segments. Thefoams with homopolymer based soft segments (VF130309 and VF190309) shownin FIG. 88 were produced as follows (VF130309):

-   -   Step 1) Firstly a mixture was made with 0.041 g of DABCO LV-33        (Airproducts), 0.120 g of bismuth neodecanoate (Bicat 8108M from        Shepherd chemicals), 0.467 g of diethanol amine (DEOA, from        Sigma), 3.056 g of poly(dimethyl siloxane) diol (DMS-s14 Gelest        Inc.), 1.633 g of polypropylene oxide (Mw=700 g/mol), 0.200 g        water and 0.1 g of surfactant (Niax L-618 from Airproducts).        These were added to a plastic flat bottomed container and were        thoroughly mixed manually for 30 sec until a homogenous mixture        was obtained.    -   Step 2) To the above mixture, 15 g of a diisocyanate prepolymer        (PPT 95A Airproducts) was added. This was then thoroughly mixed        by a mechanical stirrer for 5 seconds. The material was then        molded and cured at 70° C. for 2.5 hours and post cured at        50° C. for another 3 hours.

The foams in this example were made into dumbell shapes for tensiletesting. FIGS. 88 and 89 illustrate the difference in mechanicalbehaviour between the comparative materials indicating a favourablelowering in modulus for the triblock copolymer pre-soft-segments.

Example 7

Comparative Stability of Triblock Copolymer Soft Segment VersusHomopolymer Soft Segment

Tensile test specimens were prepared in the same manner to the materialsused in Example 4 and were subjected to accelerated aging in simulatedgastric fluid (as per United States Pharmacopeia, “USP”). The materialsproduced with the pre-synthesised triblock copolymer soft segmentsresulted in substantially improved mechanical stability in gastric fluidas compared to the urethane/urea linked homopolymer equivalent asillustrated in FIG. 90. This facilitates the use of such materials forprolonged periods in digestive and more specifically gastricenvironments.

Example 8

Preparation of Water Blown Foams

Several water blown polyurethane/urea foams were also produced withvarying PO/EO/SiO polymer block ratios. The process for preparing thefoam as described above was used.

TABLE 6 Water blown formulations incorporating siloxane containingcopolymer pre-soft-segments. Polymer block ratio (PO/EO/SiO) m:n:p DABCOBICAT DEOA H₂O 41.5:8.3:0.5 0.114 0.022 0.22 2.72 40.2:7.8:0.5 0.1140.022 0.22 2.72 37.5:7:0.5 0.114 0.022 0.22 2.72 33.5:5.7:0.5 0.1140.022 0.22 2.72 29.6:4.4:0.5 0.114 0.022 0.22 2.72 21.6:1.8:0.5 0.1140.022 0.22 2.72 19:1:0.5 0.114 0.022 0.22 2.72 29.6:4.5:1.1 0.114 0.0220.22 2.72

The results from the formulations described in Table 6 are shown inTable 7.

TABLE 7 Results from mechanical testing of foams from Table 5 Polymerblock ratio (PO/EO/SiO) m:n:p % Elongation Tensile Strength (N)41.5:8.3:0.5 233 0.46 40.2:7.8:0.5 243 0.31 37.5:7:0.5 237 0.333.5:5.7:0.5 260 0.23 29.6:4.4:0.5 320 0.23 21.6:1.8:0.5 497 0.2319:1:0.5 462 0.22 29.6:4.5:1.1 437 0.29

Example 9

Use Example

Devices for use in the gastrointestinal system have historically notbeen made from specifically designed materials. Off the shelf materialsused for application in the corrosive environment of the stomach havelimited biostability and generally lose their functionality after ashort time.

The foam of the invention can be used for production of a valve of thetype described in our US2007-0198048A, the entire contents of which areincorporated herein by reference. The valve has an open position and aclosed position. The valve will have a proximal end and a distal end.The valve material can open from the proximal direction when the actionof swallowing (liquid or solid) stretches an oriface by between 100% and3000% in circumference. The open orifice optionally closesnon-elastically over a prolonged period of time, thus mimicing thebody's natural response. The duration taken to close may be between 2and 15 sec. The material can stretch to between 100%-300% from thedistal direction when gas, liquid or solids exceeds a pre-determinedforce of between 25 cmH₂O and 60 cmH₂O. In some embodiments, thematerial absorbs less than 15% of its own mass of water at equilibrium.In some embodiments, the material loses (leaches) less than 3% of it'sown mass at equilibrium in water or alcohol. In some embodiments, thematerial loses less than 10% of its tensile strength when immersed in asimulated gastric fluid at pH 1.2 for 30 days. In some embodiments, thevalve material loses less than 25% of its % elongation when immersed ina simulated gastric fluid at pH 1.2 for 30 days.

Example 10

Valve Functional Testing

The healthy lower esophageal sphincter (LES) remains closed until anindividual induces relaxation of the muscle by swallowing and thusallowing food to pass in the antegrade direction. Additionally when anindividual belches or vomits they generate enough pressure in thestomach in the retrograde direction to overcome the valve. Ananti-reflux valve must enable this functionality when placed in thebody, thus a simple functional test is carried out to assessperformance.

It has been reported that post fundoplication patients have yieldpressures between 22-45 mmHg and that most of the patients with gastricyield pressure above 40 mmHg experienced problems belching. See Yieldpressure, anatomy of the cardia and gastro-esophageal reflux. Ismail, J.Bancewicz, J. Barow British Journal of Surgery. Vol: 82, 1995, pages:943-947. Thus, in order to facilitate belching but prevent reflux, anabsolute upper GYP value of 40 mmHg (550 mmH₂O) is reasonable. It wasalso reported that patients with visible esophagitis all have gastricyield pressure values under 15 mmHg, therefore, there is good reason toselectively target a minimum gastric yield pressure value that exceeds15 mmHg. See Id. An appropriate minimum gastric yield pressure valuewould be 15 mmHg+25% margin of error thus resulting in a minimumeffective valve yield pressure value of 18.75 mmHg or 255 mmH₂O.

The test apparatus consists of a 1 m high vertical tube as shown in FIG.91, to which is connected a peristaltic pump and a fitting that isdesigned to house the valve to be tested.

The valve to be tested is placed in a water bath at 37° C. for 30minutes to allow its temperature to equilibrate. Once the temperature ofthe valve has equilibrated it is then installed into the housing suchthat the distal closed end of the valve faces the inside of the testapparatus. The pump is then switched on at a rate of 800 ml/min to beginfilling the vertical tube. The rising column of water exerts a pressurethat forces the valve shut initially. As the pressure in the columnrises the valve reaches a point where it everts and allows the water toflow through. This point, known as the yield pressure, is then recordedand the test repeated four times.

Example 11

Rationale for Accelerated Aging of Material

Clinical Condition Being Simulated

The lower esophagus of a normal patient can be exposed to the acidiccontents of the stomach periodically without any adverse side effects.However, patients with gastro esophageal reflux disease experiencedamage to the mucosa of the lower esophagus due to increased exposure tothe gastric contents. Exposure of the lower esophagus to acidic gastriccontents is routinely measured in the clinic using dedicated pHmeasurement equipment. A typical procedure involves measuring pH over a24-hour period. The levels of acid exposure in pathological refluxdisease patients is summarised in Table 8 from six clinical references.See DeMeester T R, Johnson L F, Joseph G J, et al. Patterns ofGastroesophageal Reflux in Health and Disease Ann. Surg. October 1976459-469; Pandolfino J E, Richter J E, Ours T, et al. AmbulatoryEsophageal pH Monitoring Using a Wireless System Am. J. Gastro 2003;98:4; Mahmood Z, McMahon B P, Arfin Q, et al. Results of endoscopicgastroplasty for gastroesophageal reflux disease: a one year prospectivefollow-up Gut 2003; 52:34-9; Park P O, Kjellin T, Appeyard M N, et al.Results of endoscopic gastroplasty suturing for treatment of GERD: amulticentre trial Gastrointest endosc 2001; 53:AB115; Filipi C J, LehmanG A, Rothstein R I, et al. Transoral flexible endoscopic suturing fortreatment of GERD: a multicenter trial Gastrointest endosc 2001; 53416-22; and Arts J, Slootmaekers S Sifrim D, et al. Endoluminalgastroplication (Endocinch) in GERD patient's refractory to PPI therapyGastroenterology 2002; 122:A47.

TABLE 8 Summary of acid exposure in patients with reflux diseaseInvestigator Number of patients Details % 24 h < pH 4 DeMeester 54Combined refluxers 13.5 Pandolfino 41 Gerd 6.5 Mahmood 21 Gerd 11.11Park 142 Gerd 8.5 Filipi 64 Gerd 9.6 Arts 20 Gerd 17 Average 11.035

Key Clinical Parameters

Considering that the lower esophagus is exposed to the acidic pHexposure time for an average of 11% of the measurement period, anaccelerated aging methodology can easily be conceived. Constant exposureof a test material to the gastric contents (or USP Simulated GastricFluid—Reference USP Pharmacopeia) would represent an almost 10-foldincrease in the rate of aging. Thus the time required to simulate oneyear of exposure of the lower esophagus to the gastric contents isdescribed by equation 1.

$\begin{matrix}{{( \frac{11.035}{100} ) \times 365\mspace{14mu} {days}} = {40.28\mspace{14mu} {days}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

Clinical Rationale

Immersion of test specimens in USP Simulated gastric fluid for 40.27days at 37° C. will approximate one year's exposure of the loweresophagus to acidic gastric contents in a GERD patient's scenario.

Simulated Exposure Real Time 1 year 40.28 days 2 years 80.56 days 3years 120.84 days 

Results of accelerated stability of a valve prepared from a viscoelasticfoam of the present invention are depicted in FIGS. 92A and 92B.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

The invention is not limited to the embodiments hereinbefore describedwhich may be varied in detail.

1. A luminal valve for placing in a body lumen comprising at least fourvalve leaflets, the valve having a normally closed configuration inwhich the leaflets are engaged and an open configuration in which theleaflets are open.
 2. The luminal valve as claimed in claim 1 comprising(a) at least five valve leaflets, or (b) six valve leaflets. 3.(canceled)
 4. The luminal valve as claimed claim 1 wherein the valve isan esophageal valve.
 5. The valve as claimed in claim 1 wherein thevalve has an antegrade open configuration in which the valve leafletsare opened in response to an antegrade force to allow flow through thevalve and a retrograde open configuration in response to a retrogradeforce which is substantially larger than the antegrade force.
 6. Thevalve as claimed claim 1 wherein the valve comprises a valve body ofpolymeric material.
 7. The valve as claimed in claim 1 wherein (a) thevalve comprises an outer support region the valve comprises an outersupport region and further comprises a main body region extendingbetween the support region and the valve leaflets; or (c) the valvecomprises an outer support region, a main body region extending betweenthe support region and the valve leaflets and the main body region isgenerally concave between the outer support region and a region ofco-aption of the valve leaflets. 8.-9. (canceled)
 10. The valve asclaimed in claim 7 wherein the valve leaflets and at least portion ofthe main body region inverts to allow flow in the retrograde direction.11. The valve as claimed in claim 10 wherein, on reduction in retrogradeforces the main valve region and the valve leaflets revert to thenormally closed configuration.
 12. The valve as claimed in claim 1wherein (a) the valve leaflets have a region of co-aption, (b) the valveleaflets have a region of co-aption and the valve body is reinforced atthe region of co-aption, or (c) the valve leaflets have a region ofco-aption and the valve body is thickened at the region of co-aption.13.-14. (canceled)
 15. The valve as claimed in claim 12 wherein (a) theregion of co-aption extends for an axial length of at least 1 mm, (b)the region of co-aption extends for an axial length of from 1 mm to 5mm, or (c) the support region of the valve is thickened. 16.-18.(canceled)
 19. The valve as claimed in claim 1 wherein a pressure of 0.7mm Hg in the antegrade direction is sufficient to allow a flowratethrough the valve of 140 ml/min.
 20. The valve as claimed claim 1wherein the retrograde force required to open the valve is a pressure ofgreater than 15 mm Hg and less than 40 mm Hg.
 21. The valve as claimedclaim 6 wherein (a) the polymeric material of the valve body is of anelastic material, (b) the polymeric material of the valve body is of aviscoelastic material, (c) the polymeric material of the valve bodycomprises a foam, (d) the polymeric material of the valve body comprisesan open cell foam, or (e) the polymeric material of the valve bodycomprises a polyurethane foam. 22.-25. (canceled)
 26. The valveaccording to claim 6 wherein (a) the polymeric material is stable togastric fluid for at least about 3 months, for at least about 4 months,for at least about months, for at least about 6 months, for at leastabout 7 months, for at least about 8 months, for at least about 9months, for at least about 10 months, for at least about 11 months, orfor at least about one year, (b) the polymeric material takes up lessthan about 5%, less than about 10%, less than about 15%, less than about20%, less than about 25%, or less than about 30% by weight of water atequilibrium, (c) the polymeric material of the valve body has a percentelongation of from about 50% to about 3000%, or about 200 to about1200%, (d) the polymeric material of the valve body has a tensilestrength of from about 0.01 to about 5 MPa, or about 0.1 to about 1.0MPa, or about 0.25 to about 0.5 MPa (e) the polymeric material has aYoung's Modulus of about 0.01 to about 0.6 MPa or about 0.1 to about 0.5MPa (f) the polymeric material of the valve body has a density of fromabout 0.1 g/cm³ to about 1.5 g/cm³, or from about 0.3 to about 1.2g/cm³, or from about 0.8 to about 0.9 g/cm³, or from about 0.5 to about0.6 g/cm³, or (g) the distance between the proximal end of the supportregion of the valve body and the distal end of the valve leaflets isless than about 50 mm, or less than about 40 mm, or less than about 30mm, or less than about 25 mm. 27.-32. (canceled)
 33. The valve asclaimed in claim 6 comprising a support structure for the valve wherein(a) the valve is mounted to the support structure, (b) wherein the valvesupport region is sutured to the support structure, (c) wherein thevalve support region is bonded to the support structure, or (d) whereinthe support structure is overmoulded to the valve support region.34.-37. (canceled)
 38. The valve as claimed in claim 33 wherein (a) thesupport structure comprises a luminal prosthesis, (b) the supportstructure comprises a luminal prosthesis and the luminal prosthesisextends proximally of the valve, or (c) the support structure comprisesa luminal prosthesis and the prosthesis comprises a self expandingplastics mesh, (d) wherein anchors are adapted to extend through themesh of the prosthesis, or (e) wherein the prosthesis is adapted to beanchored to the cardia. 39.-41. (canceled)
 42. The valve as claimed inclaim 38 comprising anchors for mounting the prosthesis in situ, whereinthe anchors are optionally adapted to extend through the mesh of theprosthesis. 43.-44. (canceled)
 45. The valve as claimed in claim 7wherein (a) the length of the valve from the proximal end of the supportregion to the distal end of the valve leaflets is less than about 50 mm,less than about 40 mm, less than about 30 mm, (b) the length of thevalve is approximately 23 mm, or (c) the length of the valve isapproximately the same as the outer diameter of the support region ofthe valve. 46.-47. (canceled)
 48. A method for treating gastroesophagealreflux disease comprising placing a valve as claimed in claim 1 at adesired location, wherein the desired location is optionally across thelower esophageal sphincter. 49.-50. (canceled)
 51. The method as claimedin claim 48 wherein the valve is provided with a support structure andthe method comprises mounting the support structure at the desiredlocation, optionally comprising anchoring the support structure to thebody wall at the desired location, or comprising anchoring the supportstructure to the cardia. 52.-53. (canceled)